Non-thrombogenic materials and methods for their preparation

ABSTRACT

Non-thrombogenic materials prepared by reacting a heparin-type anticoagulant, hydroxyl, or combinations of hydroxyl and acetal groups that are part of already synthesized macromolecules having an atomic carbon-to-oxygen ratio in excess of unity, an aldehyde and an acid catalyst. The non-thrombogenic materials can be used for implanted and extracorporeal biomedical devices and prostheses intended to be used in direct contact with blood, including tubes, valves, membrane assemblies for blood dialysis and oxygenation, anesthesia-carrying tubes, etc.

United States Patent [151 3,673,612 Merrill et a1. July 4, 1972 [54]NON-THROMBOGENIC MATERIALS [56] References Cited AND METHODS FOR THEIRUNITED STATES PATENTS PREPARATION 3,549,409 12/1970 Dyck ..117/47 1Inventors Edward Merrill; P'tmk seck-Lll 3,522,346 7/1970 Chang ..424/35Wong, both of Cambridge, Mass.

. I Primary Examiner-Shep K. Rose [73] Asslgnee game-Magus Insmme ofTechnology Attorney-Thomas (00011, Martin M, Santa and Richard Fambndge, Mass. Benwm; 22 Filed: Aug. 28, 1970 5 C i 211 App]. No.267,969 I 7] T Non-thrombogenic materials prepared by reacting a heparin-Relllled Application Dill type anticoagulant, hydroxyl, or combinationsof hydroxyl and [63] Continuation-inart of Ser No 745 400 Jul 17 gmupsthat already Symhesized 1968 b do Co ti S y N macromolecules having anatomic carbon-to-oxygen ratio in 747 i E2 i gg s g igz 0 excess ofunity, an aldehyde and an acid catalyst. The nony thrombogenic materialscan be used for implanted and extracorpdreal biomedical devices andprostheses intended to be [52] used in direct contact with blood,including tubes, valves, l 5 2m! A membrane assemblies for blooddialysis and oxygenation,

4 8 224 I anesthesia-carrying tubes, etc. [51] Int. Cl ..A6lf 00, A61125/00, A61k 17/18 64 Claims, No Drgwings [58] Field ofSearch..3/1;23/258.5; 117/145;

NON-THROMBOGENIC MATERIALS AND METHODS FOR THEIR PREPARATION Thisapplication is a continuation-in-part of applications, Ser. No. 745,400filed July 17, 1968 and Ser. No. 747,789 filed July 26, 1968 both nowabandoned.

This invention relates to non-thrombogenic polymer compositionscontaining pennanently bound heparin, that are particularly useful inimplanted and extracorporeal biomedical devices and prostheses for usein direct contact with blood.

Numerous materials have been evaluated for biomedical application andhave been found to exhibit varying degrees of compatibility withmammalian blood. Membranes and solid polymeric surfaces containinghydroxyl groups which have been evaluated include hydrogels, regeneratedcellulose, cross-linked polyvinyl alcohol, partially hydrolyzedcellulose esters and poly (glycerol methacrylate) and'cellulose ascellophane which presently is the most widely used membrane material fordialysis of blood. Irrespective of the source or nature ofhydroxyl-containing membranes and surfaces, they are all contactactivating with respect to the intrinsic clotting system of blood. Forexample, hydrogels not containing an anticoagulant invariably causeblood clotting in considerably less than half an hour. Thus, it isnecessary to anticoagulate blood with heparin, citrate, or otheranticoagulants prior to contact, otherwise the blood, drawn from theliving circulation will clot within a few minutes after contact.

It is well-known that the anticoagulant heparin, a polysaccharide ofapproximate molecular weight 12,000 -l6,000 carrying sulfate andamine-sulfate groups, can be bound to a variety of positively chargedmembranes and surfaces via ionic bonding. Substances containing primary,secondary, tertiary, and quarternary ammonium groups, such asion-exchange resins, aminoethyl cellulose, cross-linked polyvinyl benzyltrimethyl ammonium chloride, etc., all bind heparin to varying degreesdepending upon the density of the surface charge and other factorsrelevant to the detailed molecular structure of the surface.

Since many otherwise useful polymers, such as cellophane, celluloseacetate and cross-linked polyvinyl alcohol, lack any positively chargedgroups with which to bind heparin, they must be chemically modified suchas by amination. Chemical modification in general is undesirable sinceit leads to lower strength, easier abrasion, and added preparationexpense. While such positively charged surfaces readily absorb heparin,upon subsequent contact with blood or blood plasma, some of the heparinis released into the plasma, presumably by ion exchange, and aftersufficiently long, e.g., days or weeks, contact with plasma, andheparinized surfaces often appear to become thrombo-genic. I

Materials with low surface free energy including silicones,polytetrafluoroethylene, lipid monolayers, etc., have been investigatedactively in a search for a non-thrombogenic materia1. While theysignificantly delay blood clotting as compared with glass and otheractive surfaces, they are thrombogenic and therefore limited to medicalengineering applications, either intraor extracorporeal, in which theblood flow is sufficiently high to prevent clotting via thecontact-activation (intrinsic) process.

The present invention provides a non-thrombogenic composition and itsmethod of preparation. The composition comprises the reaction product ofheparin, a polymeric material containing hydroxyl groups, or hydroxyland acetal groups, and an aldehyde, prepared with an acid catalyst. Thereaction product comprises heparin covalently bonded to the solidpolymeric material and is insoluble in water.

The procedure for producing the composition of this invention dependsupon whether the reaction is to be carried out as a single-phasehomogeneous reaction or as a heterogeneous 5 reaction. This in turndepends on whether the polymeric material is initially in co-solutionwith the other reagents, or whether, owing to prior network formation,to microcrystallization, or to other secondary valence forces, it is ina nonsoluble, gelled, or rubbery state. ln either embodiment, sodiumheparin or the various heparinoids, all of which are characterized by ahigh sulfate and amine sulfate content, may be used. The preferredheparin is sodium heparin with an activity exceeding 100,000 U.S.P.units/gram. Any strong watersoluble acid may be used as a catalyst at anormality of approximately 0.005 to 1.0 such as sulfuric, hydrochloric,phosphoric, or acetic acid, with sulfuric acid being preferred. Suitablemonoaldehyde reactants include formaldehyde, acetaldehyde, andbutyraldehyde, with fonnaldehyde being preferred. Suitable dialdehydereactants include glyoxal and glutaraldehyde, the latter beingpreferred.

In the homogeneous reactions during the course of reaction of amonoaldehyde and/or a dialdehyde in an acidic medium in the presence ofa heparin-type anticoagulant and hydroxyl, or hydroxyl and acetal groupsof a polymer, it is believed that the heparin becomes bonded to thepolymer through acetal and perhaps some hemiacetal bridges. Whenemploying a dialdehyde, aldehyde and acid concentrations are lower thanwhen employing a monoaldehyde so that the degree of crosslinking andgelation can be more easily controlled. When gelation proceeds toorapidly, the resultant product is too highly cross-linked and can beeasily shattered. The dialdehyde concentration is between 0.001 and 1mole dialdehyde per mole of hydroxyl, or hydroxyl plus acetal, mer unitsand acid concentration is maintained between 0.005N and 0.2N. Themonoaldehyde reactant concentration is between 0.1 and 5 molesmonoaldehyde per mole hydroxyl or hydroxyl plus acetal and the acidconcentration is maintained between 0.1N and 0.5N. When a reactantmixture of monoaldehyde and dialdehyde is used, the concentration ofthe'mixture and the acid normality used will be intermediate between theranges set forth above for either monoaldehyde or dialdehyde separately,and will be dependent upon the relative concentration of each aldehyde.The heparin-type anticoagulant is employed in concentrations to effectsubstantially uniform bonding to the polymer surface and to render thesurface nonthrombogenic. Generally, the heparin is employed inconcentrations between 0.5 and 5.0 weight percent based upon the finalsolution. Reaction temperature is regulated between about 60 and C. toobtain reaction times of from 20 minutes to 12 hours. I

Suitable soluble polymers include poly (vinyl alcohol), copolymers ofvinyl alcohol and vinyl acetate, poly (vinyl alcoholco-acetate-co-acetal), methyl cellulose, carboxy methyl cellulose, orthe like.

For convenience, a preferred process of this invention. wherein ahydrogel is formed from a hydroxyl-containing polymer initially insolution, is described with reference to a copolymer of polyvinylalcohol and polyvinyl acetate. Commercial polyvinyl alcohol having anaverage molecular weight between 5,000 and 120,000 a polyvinyl acetatecontent of from zero to 10 weight percent and containing no antioxidantor stabilizer, is preferred. Any foreign matter should be removed eitherby centrifugation or filtration of the polymer solution. For convenienceof subsequent mixing and casting, the final polymer concentration in themixture can be between 5 and 25 percent by weight. The concentration ofreagent grade formaldehyde should be between 3 and 10 weight percent, ofsodium heparin between 0.1 and 1.5 weight percent, and sulfuric acidconcentration of 0.07 to 0.4N or hydrochloric acid 0.04 to 0.1N. Thefinal mixture is heated at temperatures between 60 and 90 C. for 20minutes to 12 hours. When glutaraldehyde is used without anymonoaldehyde, its preferred concentration is between 0.02 and 7 percent,and

the acid concentration must be significantly reduced to,

between 0.005N and 0.05N. Otherwise gelation will proceed too rapidly,and the resulting product will be too highly crosslinked and fragile.

The heparin-bonded hydrogels obtained from homogeneous reactions, if notallowed to dry out, are characterized by their ability to hold, byosmotic swelling, very large quantities of water, up to parts per 1 partof polymer, while retaining a network structure to prevent their goinginto solution. When monoaldehydesare used exclusively, and the extent ofreaction is low (e.g., lower temperature, shorter times), the ultimatehydrogel is opaque at 37 C. and becomes increasingly transparent uponbeing cooled in saline (0.15M) to C. It swells greatly, increasing involume up to five fold as it is cooled from 37 to 0 C. and theswellingis reversible. The hydrogels thus prepared from monoaldehydes areexceptionally extensible with ten-fold elongation without tear beingeasily achieved. Aflerextension they recover completely, but slowly,their original dimension, suggesting a viscoelastic processcharacterizedby high internal viscous damping. More drastic reactionconditions, e.g., higher acid concentration, higher temperature, andlonger time, lead to hydrogels that are significantly less affected inswelling properties by temperature, and indeed have a lower watercontent and decreasing wettability of their surfaces.

Depending upon reaction time, aldehyde content, acid normality,temperature, the hydrogels prepared from monoaldehydes range from grossporosity such that red cells and other formed elements of blood caninvade the gel to molecularly tight" gels, obtained by drying andreswelling the highly reacted hydrogel, capable of excluding most plasmaproteins while transporting micromolecular compounds.

ln contrast, hydrogels prepared in a homogeneous reaction from adialdehyde, such as glutaraldehyde, are distinctively different in thefollowing respects:

a. They, are perfectly or nearly completely transparent;

b. They do not significantly swell or shrink when heated or cooled insaline over the range 50 to 0 C;

0. They are limited in extensibility, behaving more like an idealvulcanized rubber with low viscous damping and with characteristic quicksnap-back after extension;

d. The gel is sufficiently tightly cross-linked as to exclude all formedelements of blood, and under most conditions to exclude plasma proteins.

When bonding the. heparin to a solid polymer rather than a polymerdissolvedin water, the reaction is carried out in the presence of anacid solution so that, the hydroxyl or hydroxyl plus acetal groups ontheportion of the polymer to be reacted contain at least50 weight percentwater when in equilibrium with surrounding water or dilute salinesolution at temperatures between 0 and 50 C. Reaction of theheparin-type anticoagulant, monoaldehyde, and/or a dialdehyde also iseffected in an acid medium so that the product comprises a heparincovalently bonded to the polymer. It is believed that this bonding alsois effected through an acetal and/or hemiacetal bridge.

The acid concentration is maintained between 0.005N and 0.15N, whendialdehydes are used exclusively. The dialdehyde concentration in thesolution phase is 0.03 weight percent to 5 weight percent. When'monoaldehydes are used exclusively, their concentration is from 1weight percent to 15 weight percent and the acid concentration ismaintained between 0.05N and 0.3N. When a reactant mixture ofmonoaldehyde and dialdehyde isused, the concentration of the mixture andthe acid normality used will be intermediate between the ranges setforth above and is dependent upon the relative concentration of eachaldehyde. The heparin-type anticoagulant is employed in concentration toeffect substantially uniform bonding to the polymer surface and torender the surface nonthrombogenic. Generally, the heparin is employedin concentrations between 1 and 5 weight percent based upon the finalsolution.

Suitable solid polymer materials containing hydroxyl, or combinations ofhydroxyl and acetal groups, are those which do not dissolve when exposedto water. lnsolutility may be the result of (a)crystallization, (e.g.,cellulose), of (b) cohesion characteristics of the glassy state, (e.g.,partially saponified cellulose), (c) three-dimensional molecular networkformation as produced by free-radical polymerization of glycerylmethacrylate or by chemical cross-linking of linear,hydroxylcarryingwater soluble polymers. Cellulosic materials includecellophane in any form, cellulose acetate, cellulose acetatebutyrate,and cellulose propionate-butyrate. It will be understood that thesurface of said cellulose acetate, cellulose acetate-butyrate, andcellulose propionate-butyrate is subject to a previous saponifyingprocedure if the hydroxyl content of the original material isinsufficient to effect covalent bonding of heparin. Saponification canbe effected conveniently by maintaining the polymer in a 5 percent NaOHsolution at 60 C. for approximately 24 hours. The preferred solidpolymer is a network polymer or hydrogel previously synthesized frompolyvinyl alcohol and its copolymers with vinyl acetate such aspolyvinyl alcohol co-acetate.

In the reactive solution in which the solid polymer is soaked, thenheated, the preferred concentration of heparin is about 4 weightpercent, of aldehyde such as glutaraldehyde, 0.02 to 4 weight percent,and sufficient sulfuric acid to yield a normality of between 0.0 1 SN to0.15N. The preferred reaction temperature range is 60 to C. and thepreferred reaction time is 40 minutes to 3 hours;

Material produced from the solid polymeric starting material. by thisprocedure has no significant difference in mechanical or structuralproperties relative to the control materials from which heparin isomitted.

The compositions of this invention, whether obtained by homogeneous orheterogeneous reaction, contain permanently bound heparin and permitlong storage of human blood without the use of anticoagulants. No priorcontact with blood plasma proteins is necessary to render thecompositions of this invention non-thrombogenic. These compositions maybe readily formed into a wide variety of shapes such as membranes,tubes, rods, valves, sponge-like material, and slabs with adjacent butnon-communicating micro-channels particularly useful for blood dialysisand for blood oxygenation. in contrast to materials of the prior art,these materials may be quickly freed of excess heparin used in theirsynthesis within about 48 hours and the materials can by synthesizedsothat they have exceptional tear resistance, very high rates of waterfiltration, complete retention of plasma proteins, and numerous otherproperties of basic necessity in various biomedical applications.

Remarkably enough in the present invention, we have found that someheparin remains potent as an anticoagulant even after synthesis in thepresence of dilute sulfuric, hydrochloric, or other acids under ourpreferred conditions. It is also found that heparin decreases the rateof cross-linking of polyvinyl alcohol, suggesting direct involvement inthe-kinetics of acetal bridge formation. After completion of thereactions cited above, a significant amount of heparin is bound to thesubstrate in such a way that it cannot be eluted by strong salt (3molar) solution, indefinite washing, washing under pressure, or otherforceful means whereby molecularly entrapped or ionically bound heparincan be removed. For example, 3 molar sodium chloride solution willquantitatively remove more than 91 percent of heparin bound to any amineionexchange substrate within sixty minutes under standard conditions offlow, and ultimately will remove all heparin. The heparin content of ournon-thrombogenic materials can be well demonstrated by either the use ofS -labelled heparin followed by scintillation counting of theradioisotopes, or by the reaction characteristic of toluidine blue,which in the presence of heparin in pure water produces a brilliantlyviolet complex. By either the counting of S or by examination oftoluidine blue-stained hydrogels, or polymers, we have ascertained thatthe content of heparin remains constant after approximately twelve to 24hours of washing and no further physical or chemical procedures short oftotal destruction, as for example by prolonged exposure to strong acid,oxidizing agent, etc., will remove the heparin. Further, toluidine bluestain and S"-"- labelled heparin are found to be uniform throughout thehydrogels produced by homogeneous reaction indicating unifonnconcentration of heparin.

While the compositions described above are non-thrombogenic andtherefore useful in medical appliances designed for contact with humanblood, their use is relatively limited to special applications. Forexample, while the F-gels produced from homogeneous mixtures of heparin,polyvinyl alcohol, and formaldehyde are remarkably tough and tearresistant, if they are reacted for a sufficient time at a sufficientlyhigh temperature, a fraction of the heparin used appears to becomeinactivated, thereby rendering the process relatively uneconomical withrespect to the use of heparin.

ln contradistinction to the gels made from polyvinyl alcohol andmonoaldehydes, such as formaldehye(F-gels"), the gels made frompolyvinyl alcohol and dialdehydes such as glutaraldehyde (G-gels") aremade with very low acid concentrations and are more economical withrespect to the use of the heparin. These gels are relatively fragile.Though containing 90 percent or more water, when stressed beyond acertain value they shatter rather than tear. Various medical uses forthem still exist, especially in situations where adequate time andprecautions may be used to adapt them into a configuration in which theywill be used without stress.

Similarly, there are some disadvantages involved with the use of thesolid cellulosic polymers, e.g., cellophane and cellulose esters.Commercial cellophane, when made as dialysis tubing, consists of agrossly porous core material sandwiched between two thin-skin surfaceswhich have local imperfections. The problem with cellophane when treatedby the process described above, or in fact by any other process such assulfation, is that the skin layers tend to separate or open during andafter reaction, thereby permitting the exposure of non-heparinizedmaterial to blood at a subsequent time. Furthermore, the celluloseesters, useful as hard, rigid materials such as celluloseacetate-butyrate, present an even greater difficulty in that in theiroriginal form they are unreactive and must undergo surface hydrolysis tocreate hydroxyl groups to permit heparin bonding. We have found that itis particularly difficult uniformly to hydrolyze the surface ofcellulose ester pieces thereby to obtain uniform heparin bonding, andthat the rate of hydrolysis varies with respect to area under identicalreaction conditions, as a function of previous history of the polymer,e.g., the extent of orientation produced in it during extrusion, theplasticizer content, etc.

It is preferred to employ the process described below to prepare certaincompositions of this invention. The composition so prepared can be usedin applications as widely different as ultrafiltration membranes forblood dialysis or oxygenation and for intravenous lifeline catheters toprovide long-term nutrition to patients by direct injection into thevena cava below the right heart.

The preferred process comprises preparing a multi-layer compositionwherein only a relatively thin surface portion contains heparin bondedto the substrate. The substrate comprises or includes a cross-linkedhydrogel formed from polyvinyl alcohol or vinyl alcohol-acetatecopolymers. This substrate is prepared by reacting the soluble polymerwith a monoaldehyde in acid in the manner described above but in theabsence of heparin. A fluid surface layer containing heparin is thencoated on and bonded to the substrate layer. The composition employed toform the surface layer comprises an aldehyde, a heparin-typeanticoagulant, and an acid catalyst that is reacted to effectcross-linking in the manner described above. The surface layer may alsocontain soluble polymer which possesses hydroxyl groups. Theacetalhemiacetal-hydroxyl equilibrium on the substrate layer isreestablished to convert the previously formed acetal bonds thereon tosecondary hydroxyl groups. This can be effected coincident with applyingthe surface composition by controlling the acid concentration thereinand/or by contacting the substrate with water and/or acid prior toapplying the coating. After this equilibrium is reestablished and thesurface coating applied, the reaction proceeds to effect bonding of theheparin and soluble polymer, if any, in the surface layer through acetalor hemiacetal bonds to the substrate layer.

After reaction is complete, the composition is washed to remove excessreactants and acid. The acid concentration in the surface layer ismaintained between 0.05N and 0.5N,

preferably between 0.1N and 0.2N, to effect the desired reaction withoutdegrading a large fraction of the heparin. While operating within thepreferred acid concentration range, the desired heparin bonding to thesubstrate is attained within a short period.

The mechanical properties of the substrate material desired are obtainedby regulating the conditions leading to acetal formation from aldehydeand/or by regulating the water content of the substrate prior toreaction with the heparin-containing surface layer. Stiffness isincreased by increasing the degree of cross-linking and/or by removingwater from the substrate prior to reaction with the surface composition.Thus, the degree of water removal during formation of the substratematerial is controlled in accordance with the mechanical propertiesdesired in the final product. When the substrate material is dried toless than about 30 weight percent water, more severe conditions may beneeded to reestablish secondary hydroxyl groups on its surfaceaccessible to reaction. In this instance, the dried substrate materialmay be immersed in an acid solution, e.g., 4.0N sulfuric acid or water,prior to coating the substrate with the heparin composition to effectheparin bonding.

The preferred multi-layer compositions provide substantial advantages.They can be made without homogeneously mixing heparin in the reactionmixture'and with difierent degrees of drying to reduce the porosity inmaterials made from hydrogels and monoaldehydes. They can be prepared sothat heparin is uniformaly distributed over the blood-contactingsurface. Furthermore, they can be prepared over a wide range ofconditions in accordance with the mechanical properties desired. Theyconserve heparin and thereby reduce raw material cost.

In one aspect of this invention, when preparing a multi-layercomposition, a heparin-containing layer with dissolved polyvinyl alcoholis exposed to dialdehyde vapors, but only after a substantial portion ofthe polyvinyl alcohol in the surface layer has reacted with co-dissolvedmonoaldehyde, to avoid obtaining a brittle product. For example, theinitial reaction is allowed to proceed 15 minutes before dialdehydevapor is introduced. Then another 30 minutes or so is allowed tocomplete the reaction in the presence of dialdehyde vapor.

in another aspect of this invention, the substrate is formed by creatingthe network polymer system out of the initially homogeneous solutionaround any reinforcing material including woven or non-woven porousstructures that can be permeated by the initially homogeneous reactivesolution prior to cross-linking.

All the compositions of this invention, when fashioned into a vessel forthe in vitro incubation at 37 C. of human blood freshly drawn byvenipuncture by the Lee-White procedure, are non-thrombogenic as deducedby the following conditions that, taken together, are necessary andsuflicient:

a. Control aliquots of blood incubated in glass tubes shall clot in lessthan 7 minutes and greater than 3 minutes; incubated in siliconizedglass tubes shall clot in not less than 12 minutes.

b. Aliquots of blood placed in said material used as a comparable vesselat 37 C. shall not clot prior to 50 minutes.

0. Aliquots of blood removed from said vessel after 50 minutes andplaced in standard glass tubes shall clot within 1 minute of the controltime.

d. Aliquots of blood removed from said vessel after 50 minutes andthereupon anticoagulated with citrate, shall yield aliquots of plasmathat upon addition of thrombin will clot within 2 seconds of a control,when the control time at 37+ C. is adjusted to 14 seconds by appropriatedilution of thrombin.

The advantages gained by the composition of this invention arecompatibility and non-thrombogenicity in contact with mammalian blood,to a degree never before achieved with any substance, combined with thequalities of a separation membrane which may be utilized for oxygenationof blood and dialysis. The processes whereby these compositions areproduced have the advantage of relative simplicity compared to theprolonged reaction time and complicated reaction conditions necessarytoprovideionic binding sites for those substances in which heparin isionically bound. These same processes permit achievement ofnon-thrombogenic biomedical materials in a wide variety of shapes,simple or complicated.

The following examples illustrate the present invention and are notintended to limit the same.

EXAMPLE 1 (HOMOGENEOUS REACTION) Thirty cc of a 10 weight percentaqueous solution of pure polyvinyl alcohol (less than 0.5 percentpolyvinyl acetate) and 4 cc of formalin (37 percent formaldehyde inwater) were mixed. Six cc of one normal H 80 were added to the mixture.No heparin .was added. The mixture was evacuated to eliminate allairbubbles and placed in between concentric glass tubes. The mixture wassealed and heated at 70 C. for 50 minutes. The resulting polyvinylalcohol-formal hydrogel was washed extensively withdistilled water toextract all acid within 10 minutes and then washed in a physiologicaldialysate solution for three days. During the course of washing, thehydrogel was squeezed frequently to facilitate the extraction ofuncross-linked polymers. This plain hydrogel tubing showed a whole bloodclotting time of 40 minutes, from time of venipuncture (Lee-Whiteprocedure).

EXAMPLE 2 (HOMOGENEOUS REACTION) Forty cc of a 10 weight percent aqueoussolution of pure polyvinyl alcohol (same as in Example 1) were mixedwith 10 cc of formalin. 0.5 gram of solid sodium heparin was dissolvedto the mixture. Addition of 3 cc of 0.8N I-ICl produced in the finalsolution an acid concentrationof about 0.045N. The mixture was evacuatedand heated between concentric cylinders to form hydrogel tubing, at 60C. for 12 hours. The resulting hydrogel-heparin tubing was washed as inExample I. A piece of tubing, upon staining with toluidine blue, showeduniform brilliant purple, indicating the uniform bonding of heparin. Bycomparison, control gels containing no heparin do not stain more thantemporarily with toluidine blue, and the color is sky-blue rather thanpurple. The final tubing has a whole blood clotting time of greater than60 minutes, a thrombin time of 14 seconds and a normal prothrombin time.This hydrogel tubing has a water content of about 96 percent and poorphysical strength. Chromatographic data showed that plasma proteinleaked out through the hydrogel at a slow rate.

EXAMPLE 3 (HOMOGENEOUS REACTION) A hydrogel tube was made having exactlythe composition of Example2, except that radioactive heparin containingS was used. The labelled heparin, bonded on the hydrogel membrane, wascounted in a scintillation counter. After one day of washing in .water,no appreciable amount of heparin was eluted out from the membrane. Theamount of heparin remained constant on the membrane after the second dayof washing with water. This. firmly bonded heparin did not elute outduring a total of days of washing in water, subsequently during 3 daysof washing in 0.9 percent saline, and subsequently during 3 days ofwashing in physiological dialysate solution. That is to say, the S counton the sample remained constant within experimental error. The heparinremaining in the membrane was estimated to be at least 0.06 percentbased on polymer dry weight.

EXAMPLE 4 HOMOGENEOUS REACTION) Thirty cc of weight percent aqueoussolution of pure (as in Example 1) polyvinyl alcohol and 5 cc offormalin (37 percent formaldehyde) were mixed. Then 0.4 gram of solidsodium heparin was dissolved into the mixture. To the mixture was added6.2 cc of one normal H 50 The final solution had an acid concentrationof 0.15N. The mixture was evacuated to get rid of air bubbles and placedbetween concentric glass tubes to form tubing. The mixture was heated atC. for 60 minutes. The resulting tubing was washed as in Example 1. Thehydrogel tubing contained approximately 94 percent water. A piece ofthis tubing, upon staining with toluidine blue, showed uniform brilliantpurple. Another piece, after shaking in BM NaCl, again showed uniformbrilliant purple. This is in contrast to ionic binding of heparin onaminated polymers from which almost all heparin can be removed after awashing with 3M NaCl for an hour. This hydrogel tubing had whole bloodclotting time greater than 60 minutes. The blood which had beenincubated in it for 60 minutes when poured into a glass test tubeclotted in 6 minutes compared to a control of 7 minutes. Thrombin timeon plasma incubated in the hydrogel was 19 seconds versus a control of13 seconds. These experiments conclusively show negligible elution ofheparin upon contact of blood or plasma with hydrogel.

Permeation experiments on the hydrogel tubing (wet wall thicknessapproximately 3 .e mm at 23 C.) with whole blood plasma showed 4.6percent leaking out per 50 hours at 5 C. Since this hydrogel had a largenegative expansion coefiicient, it swelled to a great extent at 5 C. Theactual permeation rate at 37 C. is expected to be lower. Electrophoresisdone on the whole blood plasma alter'the permeation experiment showed nocomponent of any proteins missing. A flat membrane made by reacting thefinal mixture on a mercury surface had a uniform wet thickness of 79mils. The effective diffusion coefficient for sodium chloride wasmeasured through this membrane at 37 C., and equalled 1.7 10) cmlsec incomparison with a typical value to that of cuprophane which is 3.5 (10)cm /sec.

The products of this composition of hydrogel were tested repeatedly byin vitro biomedical tests. Some data are presented as follows:

Sample Whole Blood Clotting Time Glass Time II 60min 6min(7 min) III 60min 6min(7 min) 1V 80 min 4 min (5 min) V 70min 6min(6 min) VI"v min7min (6 min) Note: The values in parentheses are controls.

*Two blood samples were taken out from the hydrogel glass test. 0. 1 ccof protamine was added to one of the samples, resulting in aprolongation of glass time to 8 minutes. The absence of free heparin inthe blood is conclusively demonstrated by this test because theprotamine in total absence of heparin exhibits characteristic weakanticoagulation.

EXAMPLE 5 (HOMOGENEOUS REACTION) Thirty cc of 10 weight percent aqueoussolution of pure (as in Example 1) polyvinyl alcohol and 6 cc offonnalin (37 percent formaldehyde) were mixed. Then 0.4 gram of sodiumheparin was dissolved into it. To the mixture, 2.9 cc of 2.9 cc of 2.0Nof H 80, were addedto make the final acid concentrationabout 0.15N. Thesolution was evacuated and heated between coaxial cylinders at 80 C. for60 minutes to form a tube. The resulting hydrogel tube was washed as inExample 1. The hydrogel water content was about 93 percent by weight.This tubing had a whole blood clotting time greater than 84 minutes.After incubation in this tube for 84 minutes, blood EXAMPLE 6(HOMOGENEOUS REACTION) Sample Whole Blood Clotting Time Glass Time I 60min 4.5 min (4 min) 4.5 min ll 63 min 8.5 min (6 min) 8.5 min Note: Thecontrol times are inside parentheses. are incubated blood with additionof 0.1 cc of protamine. Normal thrombin and prothrombin times wereobserved on these tubes.

EXAMPLE 7 (HOMOGENEOUS REACTION) To a solution containing 0.4 gramsodium heparin in 4 cc of 37 percent formaldehyde, was added 1 cc of 1percent glutaraldehyde. The above mixture was stirred into anothersolution containing 25 cc of 8 percent polyvinyl alcohol and 5.8 cc of1.0N H SO The total mixture had an acid concentration of about 0.15N.This final solution was evacuated and heated between coaxial cylindersat 80 C. for 45 minutes. The resulting hydrogel after neutralizationwith dilute sodium bicarbonate solution and washing with saline, wastested repeatedly by in vitro tests. Data are presented as follows:

EXAMPLE 8 (HOMOGENEOUS REACTION) 0.3 gram of sodium heparin wasdissolved in 10 cc of 5 weight percent glutaraldehyde aqueous solution.To the mixture, 20 cc of weight percent pure polyvinyl alcohol aqueoussolution and 0.3 cc of 2ON H 50 were added. The mixture had an acidconcentration of about 0.02N. The mixture was evacuated and heatedbetween coaxial cylinders at 90 C. for 1 hour. The resulting hydrogelwas washed extensively with distilled water to extract most acid within10 minutes and then washed in daily-renewed physiological dialysatesolutions for 6 days. A piece of this tubing, upon staining withtoluidine blue showed uniform brilliant purple. The hydrogel had a watercontent of about 93 percent.

EXAMPLE 9 (HOMOGENEOUS REACTION) EXAMPLE l0 (HOMOGENEOUS REACTION) Thecomposition was exactly as in Example 9, except that 0.15 cc of 2.0N HSO was used to make the final acid concentration of about 0.01N. Afterevacuation, heating at 90 C. for 150 minutes, and washing, as in Example8, this hydrogel had a whole blood clotting time greater than 60 minutesand a normal glass time.

EXAMPLE ll (HOMOGENEOUS REACTION) The composition was exactly as inExample 9, except that 0.1 cc of 2.0N of H SO was used to make the finalacid concentration at about 0.007N. After evacuation, heating at C., for4 hours, and washing, as in Example 8, this hydrogel had a whole bloodclotting time greater than 60 minutes and a normal glass time.

EXAIWPLE l2 (HETEROGENEOUS REACTION WITH A CELLULOSIC) Cellophanedialysis tubing (Union Carbides No. 8), after extraction of itsglycerine by immersion in boiling water, was immersed into an aqueoussolution which was composed of 10 cc of 5 weight percent of sodiumheparin, 5 cc of 10 weight percent of glutaraldehyde and dilute sulfuricacid to make the final acidity 0.015N. The reaction was carried outinside a closed glass vessel placed in an oven at 90 C. for 90 minutes.After the reaction, the cellulose tubing was washed in a constantlyrenewed isotonic dialysate solution for 80 hours. The whole bloodclotting time (WBCT) of blood drawn by venipuncture into this tubing wasgreater than 60 minutes. When thereafter poured into a glass tube, theblood clotted in 3 1% minutes in comparison to a control of 4 5%minutes. Normal thrombin and partial thromboplastin times were observedon blood incubated in this tubing. Upon staining a piece of the tubingwith toluidine blue, it became brilliant purple, characteristic ofheparin.

The same reaction was carried out with S -labelled heparin. Afterwashing the reacted cellulose tubing with dialysate solution for 30hours, the S heparin was found to be constant at a level ofapproximately 2 micrograms. The tubing was then washed with 9 wt. sodiumchloride solution for 24 hours. As determined by S counting of thetubing, no heparin was removed from the cellulose. In contrast,aminoethyl or other aminated cellophane to which heparin is ionicallybonded will lose about 99 percent of its heparin upon contact with 9percent sodium chloride solution for 5 hours.

EXAMPLE l3 (HETEROGENEOUS REACTION WITH A CELLULOSIC Cellophane tubingwas treated exactly as in Example 12 except that the acidity of thesolution was 0.008N and the reaction time was minutes. After washingwith dialysate solution, the tubing showed a whole blood clotting timegreater than 60 minutes, but normal glass and thrombin times for freshblood and plasma, respectively, incubating in the tubing.

EXAMPLE l4 (HETEROGENEOUS REACTION WITH A CELLULOSIC Cellophane tubingwas reacted exactly as in Example 12 except that 10 weight percent ofheparin and 15 weight percent of glutaraldehyde solutions were used.After washing, this tubing had a whole blood clotting time greater than60 minutes, but a normal glass and thrombin time for fresh blood andplasma, respectively, incubated in the tubing.

EXAMPLE l5 (HETEROGENEOUS REACTION WITH A CELLULOSIC) The interiorsurface of injection-molded cellulose acetate tubes were firstsaponified with lpercent sodium hydroxide at 50 C. for 3 hours. Otherconditions of reaction were the same as Example 14. After washing, thesetubes, when partially filled with blood drawn by venipuncture, showedwhole blood clotting times greater than 60 minutes, but normal glass andthrombin times for fresh blood and plasma, respectively, incubated inthe tubes.

Commercially extruded cellulose acetate-butyrate tubing of 7/l6 inch ininside diameter, cut into 4 inch lengths and heated-sealed at one end,was first saponified with 5 percent NaOH solution at 60 C. for 24 hours.After washing thoroughly in water to remove free sodium hydroxide, asolution in water of 4 percent by weight heparin and 4 percent by weightglutaraldehyde, acidified with sulfuric acid to a molarity of 0.0l5M,was placed inside the tubes, with the open ends facing upward. These, inturn,were placed inside a glass vessel sealed at the top, so as toprevent escape of water vapor. The glass vessel was placed inside an airoven at 90 C. for 90 minutes.

Following washing with isotonic saline, these little tubes of celluloseacetate-butyrate were found to have whole blood clotting times in excessof 2 hours, but normal thrombin and partial thromboplastin times forplasma incubated in identically made tubes. 'Furthermore, whole bloodtaken by venipuncture, after incubation for 75 minutes in these tubes,clotted within 5 minutes when poured into a glass tube, and within 11minutes in siliconized glass, like the original controls.

EXAMPLE l7 (HETEROGENEOUS REACTION This example illustrates one methodfor practicing the preferred embodiment of this invention to form anultrafiltration membrane. A substrate compound was prepared from ahomogeneous solution of polyvinyl alcohol (PVA), 6.5 weight percent;formaldehyde, 3.5 weight percent; and sulfuric acid, 0.l5N. Thissolution was coated onto a Schleicher and Schuell No. 595 typequantitative analysis filter. Extensive penetration of the solution waseffected. The resulting composition was heated to 70 C. for 60 minutescausing the PVA to gel and become cross-linked. It was permanentlymechanically imbedded in the fibrous structure of the filter paper.

' A finishing composition was prepared from sodium heparin, 1.0 weightpercent; polyvinyl alcohol, 5.5 weight percent; for maldehyde, 7.0weight percent; and sulfuric acid sufficient to produce a normality of0.15. The finishing composition was doctored by knife onto. thegel-filter paper composition and was heated to 80 C. for 15 minutes. Dueto the sulfuric acid present, previously formed acetal bonds in thesubstrate compound probably revert to secondary hydroxyl groups, becausethe acid reestablishes the acetal-hemiacetal-hydroxyl equilibrium. Thenthe reaction probably starts to go forward again, this time involvingthe simultaneous bonding of heparin and polyvinyl alcohol in thefinishing compound to the substrate. After the first 15 minutes, theheparin-containing surface was exposed to glutaraldehyde vapor producedby vaporizing glutaraldehyde out of a 1 percent solution in water at 80C., thereby producing a very thin skin of G-gel. Vapor-phase reactionwas effected for 30 minutes and the material was then quenched. Theresulting composition comprises a reinforced membrane with a heparinizedthin surface, that excludes proteins of blood plasma, bonded to a ratherporous interior (the pores being characteristic of a well reactedF-gel), aided and abetted by additional porosity introduced from thefilter paper fibers. Typical ultrafiltration rates for this materialunder 5 lb per square inch of transmembrane pressure are 140 ml. offluid per minute per square meter when 3 percent albumin in isotonicsaline is placed on better, and 80 ml offluid per minute per squaremeter when citrated blood-bank blood was ultrafiltrated, excluding 95 to100 percent of all blood proteins.

i the high pressure sidepExclusion of albumin is 80 percent or EXAMPLEl8 HETEROGENEOUS REACTION UTILIZING NETWORK POLYMER HAVING HYDROXYL ANDACETAL GROUPS) This example provides another method for practicing thepreferred embodiment of this invention to form an ultrafiltrationmembrane. Two substrate compounds were used (instead of one as inExample 17) anda strong monofilament mesh was used together withanalytical grade filter paper to produce a strong tear resistantultrafiltration membrane. The first substrate compound (impregnatingcompound) was prepared by dissolving 2 percent by-weight polyvinylalcohol, 20 percent formaldehyde, and suflicient sulfuric acid toproduce a notmality of 0.3 in water. The filter paper was floated onthis substrate compound and immediately imbibed it from the undersurface to the upper Sul'ffiCCwA second substrate compound, or bondingcompound, was prepared by dissolving 5.5 weight percent polyvinylalcohol, 8.0 weight percent formaldehyde, and suflicient sulfuric acidto produce a normality of 0.15 in water. The second substratecomposition was spread on the upper surface of the previouslyimpregnated paper and the reinforcing monofilament mesh screen then waslaid thereon so that the second substrate composition filled theinterstices of the screen and held it in a matrix which becamehomogeneous with the filter paper underneath. Reaction was accomplishedby heating the assembly at 70 C. for 50 minutes under conditions thatprevented loss of water or formaldehyde vapor. The resulting materialwas essentially a well reacted F-gel" in which was irnbedded on one sidethe monofilament mesh screen and on the other side the filter paper. TheF-gel contained no heparin, however, and it is non-uniform by reason ofthe use of two different substrate compounds.

This bilayer structure, prepared as described above, was reversed sothat the screen was down and the paper side was up. -A finishingcompound, comprising 1.5 weight percent heparin, 5.5 percent polyvinylalcohol,'and 0.l5N sulfuricv acid, was applied in two successivecoatings, bydoctor blade, with partialevaporation in between coatings,so as to produce a uniform, pinhole-free, but nonetheless thin coatingon the surface. This finishing coating was gelled and simultaneouslybonded to the substrate by heating it to C. for 15 minutes then withglutaraldehyde vapor for 30 minutes.

The resulting membrane has high mechanical strength and consists of avery thin protein-excluding membrane containing the heparin on onesurface supported by a paper and monofilament mesh structure plus thepolyvinyl alcohol-coacetal gel therein. This membrane is useful inhemodiafiltration (a typical ultrafiltration rate for ACD blood-bankblood is 120 ml per minute per square meter; exclusion of blood proteinsis to percent).

EXAMPLE l9 (HETEROGENEOUS REACTION UTILIZING NETWORK POLYMER HAVING HYDROX YL AND ACETAL GROUPS) This example illustrates a method forobtaining a preferred embodiment of this invention wherein a catheter isproduced. A lifeline" intravenous catheter, intended specifically forlong-term support of an infant with sever defect of the alimentarycanal, was prepared as follows. A substrate layer from a compositionprepared by dissolving l.9 weight percent polyvinyl alcohol, 22.9 weightpercent formaldehyde, and sufficient sulfuric acid to give a normalityof 0.3N in water. This.composition was cased between coaxial glasscylinders to produce a hollow tube having a lumen diameter ofapproximately 0.5 mm and an external diameter of approximately 1.0 mm.In this configuration, heating was effected for minutes at 80 C. tocause gelation. The gel was rinsed, and then exposed to dryingcondiu'ons whereby it is desiccated to a final water content rangingbetween 15 percent by weight water and 1 percent by weight water. Thepartially dried F-gel tube then can be slipped off of the inner moldingcylinder. The more severe the desiccation, the tougher the finalmaterial becomes and the less reswellable it becomes.

After desiccation, the gel was allowed to rehydrate itself toequilibrium by resoaking in water. It was then allowed to undergo areversion" process to regenerate hydroxyl groups on the surface, most ofwhich was lostin the formation of cyclic and interchain acetal bonds.The gel was soaked in l-.0N sulfuric acid for hours at 50 C. It was thenwashed leaving a materialwith a surface having a significant hydroxylcontent capable of further reaction.

A surface composition was prepared by soaking 5.0 wt. percent sodiumheparin, 5.0wt. percent glutaraldehyde, and 0.1N sulfuric acid. The tubewas soaked in this finishing compound and then heated for 30 minutes at80 C. and rinsed. The heparin was covalently bonded to the tubing. Thetubing prepared according to this process has a mechanical feel rangingfrom over-cooked macaroni (no desiccation of the original gel followingits reaction) to hard, wiry material in the case of complete'desiccationof the gel prior to the reversion process and finishing compoundreaction. Optimum properties from the point of view of lifeline" use areobtained by drying the gel to about 10 weight percent water. Thisproduct can sustain 0.6 kg of tensile force without breaking. It isrelevant to note that in the desiccation process the lumen and exteriordiameter of the tubing decrease enormously.

The process of this example has general applicability in making vascularprostheses, implants of the Hakim type for hydrocephalus, aortic andmitral heart valve flaps, ball-andcage heart valves, ets.

As many apparently widely different embodiments of this invention may bemade without departing from the spirit and scope thereof, it is to beunderstood that we do not limit ourselves to the specific embodimentsthereof except as defined in the appended claims.

We claim:

1. A non-thrombogenic polymeric blood-contacting bimedical devicecomposition shapable in the form of hemodialysis tubing,hemodiafiltration membranes, hollow tube intravenous catheters, vascularprosthesis implants, heart valve and aortic and mitrao heart valve flapsand like devices and prosthesis comprising a heparin-type anticoagulantcovalently bonded through an acetal or hemiacetal bridge to a polymersurface or membrane thereof intended to lie in direct contact withblood, said bridges being formed from an aldehyde, hydroxyl groups orhydroxyl and acetal groups of said polymer and hydroxyl groups of saidanticoagulant.

2. The composition of claim 1 wherein the anticoagulant is heparin.

3. The composition of claim 1 wherein the anticoagulant is sodiumheparin.

4. The composition'of claim 1 wherein the aldehyde is formaldehyde. v v

5. The composition of claim 1 wherein the aldehyde is glutaraldehyde.

6. The composition of claim 1 wherein the polymer comprises polyvinylalcohol that has undergone previous reaction with an aldehyde and anacid to render it into a cross-linked state.

7. A process for making a non-thrombogenic polymer surface or membraneof a shaped blood-contacting biomedical appliance composition whichcomprises reacting on said shaped appliance polymer surface or membranein the presence of an acid catalyst an aldehyde, a heparin-typeanticoagulant and hydroxyl groups or combinations of hydroxyl and acetalgroups, said hydroxyl and acetal groups being constituents ofmacromolecules and selected from the group consisting of linearwater-soluble polymers, three-dimensional network polymers, and solid orrubbery matter owing its coherence to microcrystalline or othersecondary valence forces, said hydroxyl and acetal groups beinginitially in a local milieu containing at equilibrium 50 percent wateras measured in equilibrium with pure water or saline.

8. The process of making a non-thrombogenic composition according toclaim 7 wherein the polymer is a hydrogel and the anticoagulant isheparin.

9. The process of making a non-thrombogenic composition according toclaim 7 wherein the polymer is a hydrogel and the anticoagulant issodium heparin.

10. The process of making a non-thrombogenic composition according toclaim 7 wherein the polymer is a hydrogel and the aldehyde isformaldehyde.

11. The process of making a non-thrombogenic composition according toclaim 7 wherein the polymer is a hydrogel and the aldehyde isglutaraldehyde.

12. The processof making a non-thrombogenic hydrogel according to claim7 wherein the hydrogel is preparedfrom polyvinyl alcohol.

13. The process of making a non-thrombogenic composition according toclaim 7 wherein the polymer is a solid polymer and the anticoagulant issodium heparin.

14. The process of making a non-thrombogenic composition according toclaim 7 wherein the polymer is a solid polymer and the anticoagulant isheparin.

15. The process of making a non-thrombogenic composi tion according toclaim 7 wherein the polymer is a solid polymer and the aldehyde-isglutaraldehyde.

16. The process of making a non-thrombogenic composition according toclaim 7 wherein the polymer is a solid polymer and the aldehyde isformaldehyde.

17. The process of making the composition of claim 7 which comprisescontacting a polymer membrane or surface of the cross-linked hydrogelforming the base layer with a coating composition comprising anuncross-linked polymer, a heparin type anticoagulant, an aldehyde and anacid catalyst, said acid catalyst being present in sufficientconcentrations to establish an acetal-herniacetal hydroxyl equilibriumon a surface of said base layer and heating said composition to form anouter layer comprising heparin covalently bonded and to covalently bondsaid outer layer to said base layer.

18. The process of claim 17 wherein the base layer is dried to a waterconcentration of less than about 15 wt. prior to contacting the baselayer with said composition.

19. The process of claim 18 wherein the dried base layer is contactedwith an acid to establish an acetal-hemiacetalhydroxyl equilibrium priorto contacting the base layer with said composition.

20. The process of claim 17 wherein the base layer contains areinforcing material and is formed by contacting thereinforcing materialwith a base composition comprising a polymer an aldehyde and an acidcatalyst and heating said base composition to form acrosslinkedhydrogel'prior to contacting the base layer with said coatingcomposition.

21. The method of making a polymer surface of a shaped blood-contactingbiomedical appliance non-thrombogenic comprising the steps of:

selecting a water-insoluble polymeric surface thereof that contains inthe immediate vicinity of said surface at least 50 wt. water when inequilibrium with liquid water or dilute saline solutions at temperaturesbetween 0 C. and 50 C., said polymeric substance having hydroxyl groupsattached to the principal molecular chains, preparing an aqueoussolution of an aldehyde and a heparin type anticoagulant by mixing untilhomogenous, adding sufficient acid to said aldehyde and anticoagulantsolution, either prior to, concomitantly with, or subsequently tobringing said solution of said aldehyde, and anticoagulant into intimatecontact with said polymeric surface, heating said polymeric surface incontact with said solution of aldehyde, anticoagulant, and acid for aperiod of time between 30 minutes and 10 hours and a temperature between60 and C.

22. The method of making a non-thrombogenic polymer surface according toclaim 21 wherein said anticoagulant is an artificial sulfatedanticoagulant polysaccharide.

23. The method of making a non-thrombogenic polymer surface according toclaim 22 wherein said anticoagulant is heparinoid.

24. The method of making a non-thrombogenic polymer surface according toclaim 22 wherein. said anticoagulant is heparin.

25. The methodof making a non-thrombogenic polymer surface according toclaim 24 wherein said aldehyde is a dialdehyde.

26. The method of making a non-thrombogenic polymer surface according toclaim 25 wherein said dialdehyde is glutaral-dehyde.

27. The method of making a non-thrombogenic polymer surface according toclaim 26 wherein said acid is sulfuric acid.

28. The method of making a non-thrombogenic polymer surface accordingto, claim 21 wherein said polymer is crosslinked polyvinylalcohol-co-formal.

29. A non-thrombogenic polymeric blood-contacting biomedical devicecomposition shapable in the form of hemodialysis tubing,hemodiafiltration membranes, hollow tube intravenous catheters, vascularprosthesis implants, heart valve and aortic and mitrao heart valve flapsand like devices and prosthesis comprising a heparin-type anticoagulantcovalently bonded through an acetal or hemiacetal bridge to a polymersurface or membrane thereof intended to lie in direct contact with bloodselected'fromthe group consisting of a hydrogel, cellulose, cellophaneand cellulose ester, said bridges being formed from an aldehyde,hydroxyl groups or hydroxyl and acetal groups of said polymer andhydroxyl groups of said anticoagulant.

30. The composition of claim 29 wherein the anticoagulant is heparin.

31. The composition of claim 29wherein the anticoagulant is sodiumheparin.

.32. The composition of claim 29 wherein the aldehyde is formaldehyde.

33. The composition of claim 29 wherein the aldehyde is glutataldehyde;

34. A process for makinga non-thrombogenic polymer surface or membraneof a shaped blood-contacting biomedical appliance composition whichcomprises reacting on said shaped appliance polymer surface or membranein the presence of an acid catalyst an aldehyde, a heparin-typeanticoagulant and hydroxyl groups or combinations of hydroxyl and acetalgroups, said hydroxyl and acetal groups being constituents ofmacromolecules and selected from the group consisting of linearwater-soluble polymers, three-dimensional network polymers, andcellulose, cellophane, and cellulose esters, said hydroxyl and acetalgroups being initially in a local milieu containing at equilibrium 50percent water as measured in equilibrium with pure water or saline.

35. The method of making a polymer'surface of a shaped bloodcontactingbiomedical appliance non-thrombogenic comprising the steps of:

selecting a water-insoluble polymeric surface selected from the groupconsisting of cellulose, cellophane and cellulose esters that containsin the immediate vicinity of said surface at least 50 wt water when inequilibrium with liquid water or.dilute saline solutions at temperaturesbetween and 50 C., said polymeric surface having hydroxyl groups.attached to the principal molecular chains, preparing an aqueoussolution of an aldehyde and a heparin type anticoagulant by mixing untilhomogeneous, adding sufiicient acid to said aldehyde and anticoagulantsolution, either prior to, concomitantly with, or subsequently tobringing said solution of said aldehyde, and anticoagulant into intimatecontact with said polymeric surface, heating said polymeric surface incontact with said solution of aldehyde, anticoagulant, and acid for aperiod of time between 30 min. and hours and a temperature between 60and 90 C.

36. The method of making a non-.thrombogenic polymer surface accordingto claim 35 wherein said anticoagulant is an artificial sulfatedanticoagulant polysaccharide.

37. The method of making a non-thrombogenic polymer surface according toclaim 36 wherein said anticoagulant is a heparinoid.

38. The method of making a non-thrombogenic polymer surface according toclaim 35 wherein said anticoagulant is heparin.

39. The. method of making a non-thrombogenic polymer surface accordingto claim 38 wherein said aldehyde is a dialdehyde.

40. The method of making a non-thrombogenic polymer surface according toclaim 39 wherein said dialdehyde is glutar-aldehyde.

41. The method of making a non-thrombogenic polymer surface according toclaim 40 wherein said acid is sulfuric acid.

42. The process of making a non-thrombogenic composition according toclaim 34 wherein the polymer is a hydrogel and the anticoagulant isheparin.

43. The process of making a non-thrombogenic composition according toclaim 34 wherein the polymer is a hydrogel and the anticoagulant issodiumheparin.

44. The process of making a non-thrombogenic composition according toclaim 34 wherein the polymer is a hydrogel and the aldehyde isformaldehyde.

45. The process of making a non-thrombogenic composition according toclaim 34 wherein the polymer is a hydrogel and the aldehyde isglutaraldehyde.

46. The process of making a non-thrombogenic hydrogel according to claim34 wherein the hydrogel is prepared from polyvinyl alcohol.

47. The composition of claim 29 wherein the polymer comprises acopolyrner of vinyl alcohol and vinyl acetate origin ally in aqueoussolution.

48. The composition of claim 29 wherein the polymer is an incompletelysubstituted cellulose ester.

49. The process of making a non-thrombogenic composition according toclaim 34 wherein the polymer is cellulose or cellophane.

50. The process of making a non-thrombogenic composition according toclaim 34 wherein the polymer is an incompletely substituted celluloseester.

51. A multilayer. polymeric composition comprising an outer layercomprising the composition of claim 29 covalently bonded to a .baseshaped blood-contacting biomedical appliance polymer surface or membranelayer comprising a hydrogel cross-linked with an aldehyde.

52. The composition of claim 51 wherein the aldehyde in the outer layeris formaldehyde.

53. The composition of claim 51 wherein the aldehyde in the outer layeris formaldehyde and glutaraldehyde.

54. The composition of claim 51 wherein the base layer is crosslinkedwith formaldehyde.

S5. The composition of claim 51 wherein the base layer contains afibrous reinforcing material.

56. The method of making a non-thrombogenic polymer surface according toclaim 35 wherein said polymer is cellulose or cellophane, saidanticoagulant is heparin, and said aldehyde is glutaraldehyde.

57. The method of making a non-thrombogenic polymer surface according toclaim 35 wherein said polymer is an incompletely substituted celluloseester.

58. The method of making a non-thrombogenic polymer surface according toclaim 35 wherein said polymer is partially de-esterified celluloseacetate.

59. The method of making a non-thrombogenic polymer surface according toclaim 35 wherein said polymer is partially de-esterified celluloseacetate butyrate.

60. The method of making a non-thrombogenic polymer surface according toclaim 35 wherein said polymer is partially de-esterified cellulosepropionate-butyrate.

61. The method of making a non-thrombogenic polymer surface according toclaim 59 wherein said partially deesterified polymer is produced bysaponifying a surface of cellulose acetate butyrate by maintaining saidcellulose acetate butyrate in a NaOH solution at 60 C. for approximately24 hours.

62. An implantable or extracorporeal biomedical bloodcontacting shapedappliance shaped in the form of hemodialysis tubing, hemodiafiltrationmembranes, hollow tube intravenous catheters, vascular prosthesisimplants, heart valve and aortic and mitrao heart valve flaps and likedevices and prosthesis article with non-thrombogenic polymeric surfacesprepared according to claim 41 wherein said polymer is a cellophanemembrane.

63. An implantable or extracorporeal biomedical bloodcontacting shapedappliance shaped in the form of hemodialysis tubing, hemodiafiltrationmembranes, hollow tube intravenous catheters, vascular prosthesisimplants, heart valve and aortic and mitrao heart valve flaps and likedevices and prosthesis article with non-thrombogenic polymeric surfacesprepared according to claim 41 wherein said polymer is a celluloseester.

64. An implantable or extraporeal biomedical blood-contacting shapedappliance shaped in the form of hemodialysis tubing, hemodiafiltrationmembranes, hollow tube intravenous catheters, vascular prosthesisimplants, heart valve and aortic and mitrao heart valve flaps and thelike devices and prosthesis article with non-thrombogenic polymericsurfaces prepared according to claim 41 wherein said polymer is rigidcellulose acetate butyrate.

* l l I l

2. The composition of claim 1 wherein the anticoagulant is heparin. 3.The composition of claim 1 wherein the anticoagulant is sodium heparin.4. The composition of claim 1 wherein the aldehyde is formaldehyde. 5.The composition of claim 1 wherein the aldehyde is glutaraldehyde. 6.The composition of claim 1 wherein the polymer comprises polyvinylalcohol that has undergone previous reaction with an aldehyde and anacid to render it into a cross-linked state.
 7. A process for making anon-thrombogenic polymer surface or membrane of a shapedblood-contacting biomedical appliance composition which comprisesreacting on said shaped appliance polymer surface or membrane in thepresence of an acid catalyst an aldehyde, a heparin-type anticoagulantand hydroxyl groups or combinations of hydroxyl and acetal groups, saidhydroxyl and acetal groups being constituents of macromolecules andselected from the group consisting of linear water-soluble polymers,three-dimensional network polymers, and solid or rubbery matter owingits coherence to microcrystalline or other secondary valence forces,said hydroxyl and acetal groups being initially in a local milieucontaining at equilibrium 50 percent water as measured in equilibriumwith pure water or saline.
 8. The process of making a non-thrombogeniccomposition according to claim 7 wherein the polymer is a hydrogel andthe anticoagulant is heparin.
 9. The process of making anon-thrombogenic composition according to claim 7 wherein the polymer isa hydrogel and the anticoagulant is sodium heparin.
 10. The process ofmaking a non-thrombogenic composition accorDing to claim 7 wherein thepolymer is a hydrogel and the aldehyde is formaldehyde.
 11. The processof making a non-thrombogenic composition according to claim 7 whereinthe polymer is a hydrogel and the aldehyde is glutaraldehyde.
 12. Theprocess of making a non-thrombogenic hydrogel according to claim 7wherein the hydrogel is prepared from polyvinyl alcohol.
 13. The processof making a non-thrombogenic composition according to claim 7 whereinthe polymer is a solid polymer and the anticoagulant is sodium heparin.14. The process of making a non-thrombogenic composition according toclaim 7 wherein the polymer is a solid polymer and the anticoagulant isheparin.
 15. The process of making a non-thrombogenic compositionaccording to claim 7 wherein the polymer is a solid polymer and thealdehyde is glutaraldehyde.
 16. The process of making a non-thrombogeniccomposition according to claim 7 wherein the polymer is a solid polymerand the aldehyde is formaldehyde.
 17. The process of making thecomposition of claim 7 which comprises contacting a polymer membrane orsurface of the cross-linked hydrogel forming the base layer with acoating composition comprising an uncross-linked polymer, a heparin typeanticoagulant, an aldehyde and an acid catalyst, said acid catalystbeing present in sufficient concentrations to establish anacetal-hemiacetal hydroxyl equilibrium on a surface of said base layerand heating said composition to form an outer layer comprising heparincovalently bonded and to covalently bond said outer layer to said baselayer.
 18. The process of claim 17 wherein the base layer is dried to awater concentration of less than about 15 wt. % prior to contacting thebase layer with said composition.
 19. The process of claim 18 whereinthe dried base layer is contacted with an acid to establish anacetal-hemiacetal-hydroxyl equilibrium prior to contacting the baselayer with said composition.
 20. The process of claim 17 wherein thebase layer contains a reinforcing material and is formed by contactingthe reinforcing material with a base composition comprising a polymer analdehyde and an acid catalyst and heating said base composition to forma crosslinked hydrogel prior to contacting the base layer with saidcoating composition.
 21. The method of making a polymer surface of ashaped blood-contacting biomedical appliance non-thrombogenic comprisingthe steps of: selecting a water-insoluble polymeric surface thereof thatcontains in the immediate vicinity of said surface at least 50 wt. %water when in equilibrium with liquid water or dilute saline solutionsat temperatures between 0* C. and 50* C., said polymeric substancehaving hydroxyl groups attached to the principal molecular chains,preparing an aqueous solution of an aldehyde and a heparin typeanticoagulant by mixing until homogenous, adding sufficient acid to saidaldehyde and anticoagulant solution, either prior to, concomitantlywith, or subsequently to bringing said solution of said aldehyde, andanticoagulant into intimate contact with said polymeric surface, heatingsaid polymeric surface in contact with said solution of aldehyde,anticoagulant, and acid for a period of time between 30 minutes and 10hours and a temperature between 60* and 90* C.
 22. The method of makinga non-thrombogenic polymer surface according to claim 21 wherein saidanticoagulant is an artificial sulfated anticoagulant polysaccharide.23. The method of making a non-thrombogenic polymer surface according toclaim 22 wherein said anticoagulant is heparinoid.
 24. The method ofmaking a non-thrombogenic polymer surface according to claim 22 whereinsaid anticoagulant is heparin.
 25. The method of making anon-thrombogenic polymer surface according to claim 24 wherein saidaldehyde is a dialdehyde.
 26. The method of making a non-thrombogenicpolymer surface according to claim 25 wherein said dialdehyde isglutarAl-dehyde.
 27. The method of making a non-thrombogenic polymersurface according to claim 26 wherein said acid is sulfuric acid. 28.The method of making a non-thrombogenic polymer surface according toclaim 21 wherein said polymer is cross-linked polyvinylalcohol-co-formal.
 29. A non-thrombogenic polymeric blood-contactingbiomedical device composition shapable in the form of hemodialysistubing, hemodiafiltration membranes, hollow tube intravenous catheters,vascular prosthesis implants, heart valve and aortic and mitrao heartvalve flaps and like devices and prosthesis comprising a heparin-typeanticoagulant covalently bonded through an acetal or hemiacetal bridgeto a polymer surface or membrane thereof intended to lie in directcontact with blood selected from the group consisting of a hydrogel,cellulose, cellophane and cellulose ester, said bridges being formedfrom an aldehyde, hydroxyl groups or hydroxyl and acetal groups of saidpolymer and hydroxyl groups of said anticoagulant.
 30. The compositionof claim 29 wherein the anticoagulant is heparin.
 31. The composition ofclaim 29 wherein the anticoagulant is sodium heparin.
 32. Thecomposition of claim 29 wherein the aldehyde is formaldehyde.
 33. Thecomposition of claim 29 wherein the aldehyde is glutataldehyde.
 34. Aprocess for making a non-thrombogenic polymer surface or membrane of ashaped blood-contacting biomedical appliance composition which comprisesreacting on said shaped appliance polymer surface or membrane in thepresence of an acid catalyst an aldehyde, a heparin-type anticoagulantand hydroxyl groups or combinations of hydroxyl and acetal groups, saidhydroxyl and acetal groups being constituents of macromolecules andselected from the group consisting of linear water-soluble polymers,three-dimensional network polymers, and cellulose, cellophane, andcellulose esters, said hydroxyl and acetal groups being initially in alocal milieu containing at equilibrium 50 percent water as measured inequilibrium with pure water or saline.
 35. The method of making apolymer surface of a shaped blood-contacting biomedical appliancenon-thrombogenic comprising the steps of: selecting a water-insolublepolymeric surface selected from the group consisting of cellulose,cellophane and cellulose esters that contains in the immediate vicinityof said surface at least 50 wt % water when in equilibrium with liquidwater or dilute saline solutions at temperatures between 0* and 50* C.,said polymeric surface having hydroxyl groups attached to the principalmolecular chains, preparing an aqueous solution of an aldehyde and aheparin type anticoagulant by mixing until homogeneous, addingsufficient acid to said aldehyde and anticoagulant solution, eitherprior to, concomitantly with, or subsequently to bringing said solutionof said aldehyde, and anticoagulant into intimate contact with saidpolymeric surface, heating said polymeric surface in contact with saidsolution of aldehyde, anticoagulant, and acid for a period of timebetween 30 min. and 10 hours and a temperature between 60* and 90* C.36. The method of making a non-thrombogenic polymer surface according toclaim 35 wherein said anticoagulant is an artificial sulfatedanticoagulant polysaccharide.
 37. The method of making anon-thrombogenic polymer surface according to claim 36 wherein saidanticoagulant is a heparinoid.
 38. The method of making anon-thrombogenic polymer surface according to claim 35 wherein saidanticoagulant is heparin.
 39. The method of making a non-thrombogenicpolymer surface according to claim 38 wherein said aldehyde is adialdehyde.
 40. The method of making a non-thrombogenic polymer surfaceaccording to claim 39 wherein said dialdehyde is glutaraldehyde.
 41. Themethod of making a non-thrombogenic polymer surface according to claim40 wherein said acid is sulfuric acid.
 42. The process of making anon-thrombogeniC composition according to claim 34 wherein the polymeris a hydrogel and the anticoagulant is heparin.
 43. The process ofmaking a non-thrombogenic composition according to claim 34 wherein thepolymer is a hydrogel and the anticoagulant is sodium heparin.
 44. Theprocess of making a non-thrombogenic composition according to claim 34wherein the polymer is a hydrogel and the aldehyde is formaldehyde. 45.The process of making a non-thrombogenic composition according to claim34 wherein the polymer is a hydrogel and the aldehyde is glutaraldehyde.46. The process of making a non-thrombogenic hydrogel according to claim34 wherein the hydrogel is prepared from polyvinyl alcohol.
 47. Thecomposition of claim 29 wherein the polymer comprises a copolymer ofvinyl alcohol and vinyl acetate originally in aqueous solution.
 48. Thecomposition of claim 29 wherein the polymer is an incompletelysubstituted cellulose ester.
 49. The process of making anon-thrombogenic composition according to claim 34 wherein the polymeris cellulose or cellophane.
 50. The process of making a non-thrombogeniccomposition according to claim 34 wherein the polymer is an incompletelysubstituted cellulose ester.
 51. A multilayer polymeric compositioncomprising an outer layer comprising the composition of claim 29covalently bonded to a base shaped blood-contacting biomedical appliancepolymer surface or membrane layer comprising a hydrogel cross-linkedwith an aldehyde.
 52. The composition of claim 51 wherein the aldehydein the outer layer is formaldehyde.
 53. The composition of claim 51wherein the aldehyde in the outer layer is formaldehyde andglutaraldehyde.
 54. The composition of claim 51 wherein the base layeris crosslinked with formaldehyde.
 55. The composition of claim 51wherein the base layer contains a fibrous reinforcing material.
 56. Themethod of making a non-thrombogenic polymer surface according to claim35 wherein said polymer is cellulose or cellophane, said anticoagulantis heparin, and said aldehyde is glutaraldehyde.
 57. The method ofmaking a non-thrombogenic polymer surface according to claim 35 whereinsaid polymer is an incompletely substituted cellulose ester.
 58. Themethod of making a non-thrombogenic polymer surface according to claim35 wherein said polymer is partially de-esterified cellulose acetate.59. The method of making a non-thrombogenic polymer surface according toclaim 35 wherein said polymer is partially de-esterified celluloseacetate butyrate.
 60. The method of making a non-thrombogenic polymersurface according to claim 35 wherein said polymer is partiallyde-esterified cellulose propionate-butyrate.
 61. The method of making anon-thrombogenic polymer surface according to claim 59 wherein saidpartially de-esterified polymer is produced by saponifying a surface ofcellulose acetate butyrate by maintaining said cellulose acetatebutyrate in a 5% NaOH solution at 60* C. for approximately 24 hours. 62.An implantable or extracorporeal biomedical blood-contacting shapedappliance shaped in the form of hemodialysis tubing, hemodiafiltrationmembranes, hollow tube intravenous catheters, vascular prosthesisimplants, heart valve and aortic and mitrao heart valve flaps and likedevices and prosthesis article with non-thrombogenic polymeric surfacesprepared according to claim 41 wherein said polymer is a cellophanemembrane.
 63. An implantable or extracorporeal biomedicalblood-contacting shaped appliance shaped in the form of hemodialysistubing, hemodiafiltration membranes, hollow tube intravenous catheters,vascular prosthesis implants, heart valve and aortic and mitrao heartvalve flaps and like devices and prosthesis article withnon-thrombogenic polymeric surfaces prepared according to claim 41wherein said polymer is a cellulose ester.
 64. An implantable orextraporeal biomedical blood-contacting shaped appliance shaped in theform of hemodialysis tubing, hemodiafiltration membranes, hOllow tubeintravenous catheters, vascular prosthesis implants, heart valve andaortic and mitrao heart valve flaps and the like devices and prosthesisarticle with non-thrombogenic polymeric surfaces prepared according toclaim 41 wherein said polymer is rigid cellulose acetate butyrate.